The genetics of FOP

Posted by Karen - September 17th, 2016

I was recently in a bookstore and looking to spend a gift card when I stumbled on an interesting item, which I bought. Science nerd that I am, I’ve been finding this book absolutely fascinating. It’s called “The Gene: An Intimate History”, and it’s by Siddhartha Mukherjee (no, I am not getting paid to say this, LOL). The book is all about the history of discoveries connected to the gene. One paragraph so far particularly stood out to me. In discussing the disease sickle cell anemia, Dr. Mukherjee had this to say:

“It was a Rube Goldberg disease. A change in the sequence of a gene caused the change in the sequence of a protein; that warped its shape; that shrank a cell; that clogged a vein; that jammed the flow; that racked the body (that genes built). Gene, protein, function, and fate were strung in a chain: one chemical alteration in one base pair in DNA was sufficient to ‘encode’ a radical change in human fate.” (Scribner, New York, 2016, p. 171)

Change a few details, and Mukherjee could have been talking about my daughter’s medical condition, fibrodysplasia ossificans progressiva (FOP). This is exactly the type of chain of events which exists in FOP.

Here's what FOP does to the skeletons of FOP patients.

Here’s what FOP does to the soft tissues and skeletons of FOP patients.

Now, people often ask me about the particulars of FOP, and how it occurs. Reading the gene history book has inspired me to try my hand at describing it. I’m going to give it a try, in question-and-answer form (NOTE – my scientific knowledge is based on what I’ve learned from high school and university courses, and what I’ve read – but I’m no scientist myself – apologizing in advance if I make any errors).

Here goes…

Q: How did your daughter get FOP?  A: She was born with it; FOP is a genetic condition.

Q: Does that mean she has a problem with her chromosomes, like someone who has Down syndrome?  A: Nope. All cells in the human body contain chromosomes, which are structures containing instructions for the development and maintenance of the body. The standard number of human chromosomes is 23 pairs, for a total of 46 chromosomes (one inherited from the person’s mother; one from the father). There is nothing unusual about the number or shape of chromosomes in a person with FOP.

Q: If it’s not a chromosomal thing, then where’s the difference in someone who has FOP?  A: Each chromosome contains a vast number of genes, which are tiny “packages” which each contain the instructions for a particular function of the human body. Again, there’s nothing atypical about the type or number of genes present in a person with FOP. It’s what’s inside one of those many thousands of genes which causes FOP. You see, there is a gene located on chromosome 2 which exists to encode a protein called ACVR1, a protein made up of 509 amino acids. In people with FOP, one, just ONE of those amino acids in the ACVR1 protein is different than it’s supposed to be, as the result of a tiny, pinpoint mutation in the gene. Over 95% of people with FOP have that amino acid switch, which is histidine in place of arginine, at position 206 (less than 5% of people with FOP have an amino acid substitution at a different location on the protein).

An artist's conception of DNA

An artist’s conception of DNA, the molecules which carry information in genes. 

Q: Are you saying that all the stuff FOP does is caused by that one mutation in the ACVR1 gene?  A: Yes. All of it. Because of the substitution of the wrong amino acid, this alters the functioning of the protein, and down the line ultimately leads to formation of bone in soft tissues outside the skeleton, where it should not occur. In addition, it causes a grab bag of various other symptoms (which exist in varying degrees in different people), including the typical bent-and-slightly shrunken great toe, various other skeletal abnormalities, mild to moderate hearing loss, gastrointestinal complaints, less body hair than average, a tendency to develop osteoarthritis, and some other differences. Very much like sickle cell anemia, which is also caused by the substitution of a single amino acid in a particular protein, FOP definitely “enacts a radical change in human fate” (to quote Dr. Mukherjee again).

Q: Did your daughter inherit FOP from an ancestor?  A: Nope.

Q: How do you know her FOP isn’t inherited? Couldn’t it have come from a many-times-great grandparent somewhere back in time?  A: The only way FOP can be inherited is if you get it from a parent who has FOP. Remember how each person has pairs of chromosomes, one inherited from each parent? Because there are matching pairs of chromosomes, each gene also has a match, and the two versions of the gene are referred to as “alleles”. The body has to choose which of the two alleles to use, and there are two types of alleles – dominant and recessive. If there’s a dominant allele available, that one is ALWAYS chosen. A recessive allele will only be chosen if the person inherited a recessive allele from both parents, and there is no dominant allele present. Diseases caused by recessive alleles can indeed be inherited down through the generations sporadically, as in the case with hemophilia – remember Alexis, the last prince of Imperial Russia, who inherited hemophilia as a result of being the great-grandson of Queen Victoria, a carrier of the recessive hemophilia gene? The FOP allele, as it happens, is dominant. So, if a person has FOP which was inherited, that means the person MUST have received the FOP allele from a parent who has the allele, and that parent would definitely have FOP because of the allele being dominant.

Q: Well, you and your husband obviously don’t have FOP, so Miranda obviously didn’t inherit it. Where did it come from?  A: In this situation, as in the vast majority of cases, Miranda’s FOP was caused by a spontaneous, random genetic mutation at or shortly after conception. In other words, it’s a completely unpredictable fluke. These kinds of flukes can sometimes be good, and can spread through a population – for example, several thousand years ago, a mutation arose which allowed Europeans to digest lactose after infancy, meaning that children and adults with the mutation could eat dairy foods. Since dairy was (apparently) readily available, this was a helpful mutation and it spread far and wide, at least in Europe. Now, how about FOP? Well, not so much a good mutation, and because most people with FOP don’t have their own children, FOP is not a condition which is ever likely to spread far and wide by inheritance.

Q: What if you had another baby; would that baby have FOP as well?  A: That’s pretty darn unlikely. The FOP mutation seems to occur randomly in about 1 out of every 2 million people, and the odds of that happening again in one family – other than in identical twins, which come from a single fertilized egg – are generally really, REALLY low. Now that being said, apparently there are some rare instances in which one parent or the other doesn’t have FOP themself, but for an unknown reason does have in their body a high number of mutated gametes (sex cells). In such a parent, the probability of having another child with FOP would obviously be higher than the standard 1 in 2 million. I did hear of one case in which 2 people without FOP had a child with FOP, and then divorced, and then when the mother got remarried to another man without FOP, she and her new husband had a baby with FOP. Now, I don’t know how commonly this occurs, but from what I’ve heard it’s a very rare situation. Still, if I was planning on having another baby – which I am not – I would definitely want to talk to a medical geneticist about this possibility.

Q: If scientists know where the FOP mutation is located, can’t they fix it or at least change its function?  A: Not yet… But since the FOP gene discovery, research has proceeded in leaps and bounds. There are currently 2 potential FOP medications in clinical trials, each of which directly affects gene functioning, and I hear there are a few more in pre-clinical development. Maybe 1 or more of these possible drugs will be successful… We’re getting there!

OK, that’s it. Thanks for reading my rambling epic blog…

 

PS – If you’d like to donate to fund FOP research, please go to the website of the Canadian FOP Network (www.cfopn.org) or the International FOP Association (www.ifopa.org). There are also FOP charities in other countries, and those are good choices too. Thanks!

One Response to “The genetics of FOP”

  1. Susie says:

    WOW. This is awrsome. I think you did a great job explaining FOP.



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